Multiple drug-eluting coronary artery stent for percutaneous coronary artery intervention

Abstract

The present invention relates to a combination of agents, including an anti-proliferative agent, an anti-inflammatory agent, an anti-growth factor, and an extracellular matrix (ECM) molecule coated on a stent to prevent acute and subacute thrombosis, enhance endothelial in-growth, and prevent neointimal hyperplasia, and/or suppress neovascularization, and thereby reduce restenosis rates for drug eluting stents. The present invention also relates to methods of using such multiple drug eluting stents for the treatment of heart disease and other vascular conditions.

1 . A tubular vascular implant comprising;
 a) a first outer layer coating comprising an anti-proliferative agent and an anti-inflammatory agent;   b) a second middle layer coating comprising at least one anti-growth factor agent; and   c) a third bottom layer coating comprising at least one non-thrombogenic extracellular matrix (ntECM) molecule;   wherein the first outer layer coating is formulated for immediate and sustained release of the anti-proliferative agent and the anti-inflammatory agent upon implantation and the second middle layer coating is formulated for delayed and sustained release of the at least one anti-growth factor agent, and wherein the at least one ntECM molecule is permanently affixed to one or more surfaces of the implant.   
   
   
       2 . The tubular vascular implant of  claim 1 , wherein the middle layer coating intercalates into the third bottom layer. 
   
   
       3 . The tubular vascular implant of  claim 2 , wherein the at least one anti-growth factor agent is covalently bound to one or more surfaces of the implant. 
   
   
       4 . The tubular vascular implant of  claim 1 , wherein the at least one anti-growth factor agent is covalently bound to one or more polymers coating the implant. 
   
   
       5 . The tubular vascular implant of  claim 1 , wherein the anti-proliferative agent is selected from the group consisting of paclitaxel, actinomycin, a taxane, daunorubicin, methotrexate, cyclophosphamide, bleomycin, busufane, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, halofuginone, adriamycin, actinomycin and mutamycin; endostatin, angiostatin, and thymidine kinase inhibitors. 
   
   
       6 . The tubular vascular implant of  claim 5 , wherein the anti-proliferative agent is paclitaxel. 
   
   
       7 . The tubular vascular implant of  claim 1 , wherein the anti-inflammatory agent is and calcineurin inhibitor. 
   
   
       8 . The tubular vascular implant of  claim 7 , wherein the anti-inflammatory agent is selected from the group consisting of sirolimus, tacrolimus, everolimus, and zotatrolimus. 
   
   
       9 . The tubular vascular implant of  claim 7 , wherein the anti-inflammatory agent is sirolimus. 
   
   
       10 . The tubular vascular implant of  claim 1 , wherein the at least one anti-growth agent is selected from the group consisting of an anti-VEGF polyclonal or monoclonal antibody and an anti-PDGF polyclonal or monoclonal antibody, or a combination thereof. 
   
   
       11 . The tubular vascular implant of  claim 10 , wherein the at least one anti-growth agent is an anti-VEGF monoclonal antibody. 
   
   
       12 . The tubular vascular implant of  claim 10 , wherein the at least one anti-growth agent is an anti-PDGF monoclonal antibody. 
   
   
       13 . The tubular vascular implant of  claim 1 , wherein the at least one ntECM molecule is selected from the group consisting of laminen, heparin, heparin sulfate proteoglycan (HSP), elastin, and fibronectin, chondroitin, or a combination thereof. 
   
   
       14 . The tubular vascular implant of  claim 13 , wherein the at least one ntECM molecule is fibronectin. 
   
   
       15 . The tubular vascular implant of  claim 1 , wherein the tubular vascular implant is a stent. 
   
   
       16 . The tubular vascular implant of  claim 1 , wherein the coatings are on the outer surface of the implant. 
   
   
       17 . The tubular vascular implant of  claim 1 , wherein the coatings are at the ends of the implant. 
   
   
       18 . The tubular vascular implant of  claim 1 , wherein coatings are at one end of the implant. 
   
   
       19 . A tubular vascular implant comprising;
 a) a first outer layer coating comprising paclitaxel and sirolimus; and   b) a second middle layer coating comprising at least one anti-growth factor agent,   wherein the first outer layer coating is formulated for immediate and sustained release of the paclitaxel and sirolimus upon implantation and the second middle layer coating is formulated for delayed and sustained release of the at least one anti-growth factor agent.   
   
   
       20 . The tubular vascular implant of  claim 19 , further comprising a third bottom layer coating comprising at least one non-thrombogenic extracellular matrix (ntECM) molecule, wherein the at least one ntECM molecule is permanently affixed to one or more surfaces of the implant. 
   
   
       21 . The tubular vascular implant of  claim 20 , wherein the middle layer coating intercalates into the third bottom layer. 
   
   
       22 . The tubular vascular implant of  claim 20 , wherein the at least one anti-growth factor agent is covalently bound to one or more surfaces of the implant. 
   
   
       23 . The tubular vascular implant of  claim 19 , wherein the at least one anti-growth factor agent is covalently bound to one or more polymers coating the implant. 
   
   
       24 . The tubular vascular implant of  claim 19 , wherein the at least one anti-growth agent is selected from the group consisting of an anti-VEGF polyclonal or monoclonal antibody and an anti-PDGF monoclonal or polyclonal antibody, or a combination thereof. 
   
   
       25 . The tubular vascular implant of  claim 24 , wherein the at least one anti-growth agent is an anti-VEGF monoclonal antibody. 
   
   
       26 . The tubular vascular implant of  claim 24 , wherein the at least one anti-growth agent is an anti-PDGF monoclonal antibody. 
   
   
       27 . The tubular vascular implant of  claim 19 , wherein the at least one ntECM molecule is selected from the group consisting laminen, heparin, heparin sulfate proteoglycan (HSP), elastin, and fibronectin, chondroitin, or a combination thereof. 
   
   
       28 . The tubular vascular implant of  claim 27 , wherein the at least one ntECM molecule is fibronectin. 
   
   
       29 . The tubular vascular implant of  claim 19 , wherein the tubular vascular implant is a stent. 
   
   
       30 . The tubular vascular implant of  claim 19 , wherein the coatings are on the outer surface of the implant. 
   
   
       31 . The tubular vascular implant of  claim 19 , wherein the coatings are at the ends of the implant. 
   
   
       32 . The tubular vascular implant of  claim 19 , wherein coatings are at one end of the implant. 
   
   
       33 . A method of preventing target lesion restenosis (TLR) or target vessel restenosis (TVR) in a subject with clogged heart arteries comprising inserting a tubular vascular implant, wherein the implant comprises:
 a) a first outer layer coating comprising an anti-proliferative agent and an anti-inflammatory agent;   b) a second middle layer coating comprising at least one anti-growth factor agent; and   c) a third bottom layer coating comprising at least one non-thrombogenic extracellular matrix molecule (ntECM);   wherein the first outer layer coating is formulated for immediate release of the anti-proliferative agent and the anti-inflammatory agent upon implantation and the second middle layer coating is formulated for delayed release of the at least one anti-growth factor agent, and wherein the at least one ntECM molecule is permanently affixed to one or more surfaces of the implant.   
   
   
       34 . The method of  claim 33 , wherein the middle layer coating intercalates with the third bottom layer. 
   
   
       35 . The method of  claim 34 , wherein the at least one anti-growth factor agent is covalently bound to one or more surfaces of the implant. 
   
   
       36 . The method of  claim 33 , wherein the at least one anti-growth factor agent is covalently bound to one or more polymers coating the implant. 
   
   
       37 . The method of  claim 33 , wherein the anti-proliferative agent is selected from the group consisting of paclitaxel, actinomycin, a taxane, daunorubicin, methotrexate, cyclophosphamide, bleomycin, busufane, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, halofuginone, adriamycin, actinomycin and mutamycin; endostatin, angiostatin, and thymidine kinase inhibitors. 
   
   
       38 . The method of  claim 37 , wherein the anti-proliferative agent is paclitaxel. 
   
   
       39 . The method of  claim 33 , wherein the anti-inflammatory agent is a calcineurin inhibitor. 
   
   
       40 . The method of  claim 39 , wherein the anti-inflammatory agent is selected from the group consisting of sirolimus, tacrolimus, everolimus, and zotatrolimus. 
   
   
       41 . The method of  claim 39 , wherein the anti-inflammatory agent is sirolimus. 
   
   
       42 . The method of  claim 33 , wherein the at least one anti-growth agent is selected from the group consisting of an anti-VEGF polyclonal or monoclonal antibody and an anti-PDGF polyclonal or monoclonal antibody, or a combination thereof. 
   
   
       43 . The method of  claim 42 , wherein the at least one anti-growth agent is an anti-VEGF monoclonal antibody. 
   
   
       44 . The method of  claim 42 , wherein the at least one anti-growth agent is an anti-PDGF monoclonal antibody. 
   
   
       45 . The method of  claim 26 , wherein the at least one ntECM molecule is selected from the group consisting of laminen, heparin, heparin sulfate proteoglycan, elastin, and fibronectin, or a combination thereof. 
   
   
       46 . The method of  claim 45 , wherein the at least one ntECM molecule is fibronectin. 
   
   
       47 . The method of  claim 33 , wherein the tubular vascular implant is a stent.